Preclinical Pharmacology Section, Behavioral Neuroscience Research Branch, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, Baltimore, MD 21224, USA.
Br J Pharmacol. 2012 Apr;165(8):2539-48. doi: 10.1111/j.1476-5381.2011.01467.x.
The fatty acid amide hydrolase inhibitor URB597 can reverse the abuse-related behavioural and neurochemical effects of nicotine in rats. Fatty acid amide hydrolase inhibitors block the degradation (and thereby magnify and prolong the actions) of the endocannabinoid anandamide (AEA), and also the non-cannabinoid fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). OEA and PEA are endogenous ligands for peroxisome proliferator-activated receptors alpha (PPAR-α). Since recent evidence indicates that PPAR-α can modulate nicotine reward, it is unclear whether AEA plays a role in the effects of URB597 on nicotine reward.
A way to selectively increase endogenous levels of AEA without altering OEA or PEA levels is to inhibit AEA uptake into cells by administering the AEA transport inhibitor N-(4-hydroxyphenyl)-arachidonamide (AM404). To clarify AEA's role in nicotine reward, we investigated the effect of AM404 on conditioned place preference (CPP), reinstatement of abolished CPP, locomotor suppression and anxiolysis in an open field, and dopamine elevations in the nucleus accumbens shell induced by nicotine in Sprague-Dawley rats.
AM404 prevented the development of nicotine-induced CPP and impeded nicotine-induced reinstatement of the abolished CPP. Furthermore, AM404 reduced nicotine-induced increases in dopamine levels in the nucleus accumbens shell, the terminal area of the brain's mesolimbic reward system. AM404 did not alter the locomotor suppressive or anxiolytic effect of nicotine.
These findings suggest that AEA transport inhibition can counteract the addictive effects of nicotine and that AEA transport may serve as a new target for development of medications for treatment of tobacco dependence.
This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7.
脂肪酸酰胺水解酶抑制剂 URB597 可逆转尼古丁在大鼠中的滥用相关行为和神经化学作用。脂肪酸酰胺水解酶抑制剂可阻断内源性大麻素大麻素（AEA）的降解（从而放大和延长其作用），还可阻断非大麻素脂肪酸乙醇酰胺油酰乙醇酰胺（OEA）和棕榈酰乙醇酰胺（PEA）的降解。OEA 和 PEA 是过氧化物酶体增殖物激活受体 α（PPAR-α）的内源性配体。由于最近的证据表明 PPAR-α 可以调节尼古丁的奖赏，因此尚不清楚 AEA 是否在 URB597 对尼古丁奖赏的作用中发挥作用。
一种选择性增加内源性 AEA 水平而不改变 OEA 或 PEA 水平的方法是通过给予 AEA 转运抑制剂 N-（4-羟基苯基）-花生四烯酰胺（AM404）来抑制 AEA 进入细胞的摄取。为了阐明 AEA 在尼古丁奖赏中的作用，我们研究了 AM404 对条件性位置偏爱（CPP）、已消除 CPP 的复燃、在开放场中的运动抑制和焦虑、以及尼古丁在 Sprague-Dawley 大鼠中引起的伏隔核壳多巴胺升高的影响。
AM404 阻止了尼古丁诱导的 CPP 的发展，并阻碍了尼古丁诱导的已消除 CPP 的复燃。此外，AM404 降低了尼古丁诱导的伏隔核壳中多巴胺水平的升高，伏隔核壳是大脑中边缘奖赏系统的终末区域。AM404 不改变尼古丁的运动抑制或焦虑作用。
这些发现表明 AEA 转运抑制可以对抗尼古丁的成瘾作用，并且 AEA 转运可能成为开发用于治疗烟草依赖的药物的新靶标。
本文是关于生物和医学中的大麻素的主题部分的一部分。要查看该部分中的其他文章，请访问 http://dx.doi.org/10.1111/bph.2012.165.issue-8。要查看生物和医学中的大麻素的第一部分，请访问 http://dx.doi.org/10.1111/bph.2011.163.issue-7。
